1. Field of the Invention
The present invention relates to a heat shock protein inducer, and more particularly to a heat shock protein inducer which is useful in preventing and treating damage to the myocardial cells from ischemia and perfusion.
2. Related Art
Ischemic disease (coronary heart disease) is caused by narrowing of the coronary artery. For example, in angina pectoris narrowing of the coronary artery leads to decreased blood flow volume, depriving the cardiac muscle of oxygen (ischemia) and depressing cardiac function. If this constriction (obstruction) of the coronary artery progresses, the result is myocardial infarction and necrosis of the heart muscle, and if necrosis is sufficiently widespread the heart ceases to function as a pump and death results.
When the obstructed coronary artery is reperfused in an effort to rescue cases of myocardial infarction, damage to the myocardial cells often results and has been known to cause myocardial failure (ischemia/reperfusion injury).
Heat shock proteins (abbreviated hereunder as “HSP”) have been reported to have a cardioprotective function which alleviates ischemia/reperfusion injury. Namely, it has been reported that when myocardial cells are subjected to thermal stress or oxidation stress, heat shock proteins are expressed which confer ischemia resistance to the myocardial cells. Heat shock proteins are a family of endogenous protective proteins which are generated by various kinds of stress, such as heat shock (hyperthermia) or oxidation stress (hypoxia, hydrogen peroxide) (Bejamin IJ, McMillan D R. Stress (heat shock) proteins molecular chaperones in cardiovascular biology and disease. Circ Res 1998; 83:117-132).
For example, it has been reported that whole-body hyperthermia 24 hours before the onset of ischemic disease is protective against ischemia/reperfusion injury and is associated with proportional induction of shock protein (HSP70) expression (Hutter M M, Sieveres R E, Barbosa V et al. Heat-shock protein induction in rat hearts: a direct correlation between the amount of heat-shock protein induced and the degree of myocardial infarction. Circulation 1994; 89:355-360).
It has also been shown that ischemia resistance is high in myogenic cells and transgenic rats in which HSP70 is overexpressed (Mestril R, Chi SH, Sayen M R et al. Expression of inducible stress protein in rat heart myogenic cells confers protection against simulated ischemia-induced injury. J Clin Invest 1994: 93:759-767).
With this in view, therapies have been attempted involving the administration of heat shock protein inducers, which promote (induce) the expression of heat shock proteins in the heart (Morris S D, Cumming D E, Latchman D S et al. Specific induction of the 70-kD heat stress proteins by the tyrosine kinase inhibitor Herbimycin-A protects rat neonatal cardiomyocytes. J Clin Invest 1996; 97:706-712; Maulik N, Engelman R M, Wei Z et al. Drug-induced heat shock preconditioning improves postischemic ventricular recovery after cardiopulmonary bypass. Circulation 1995; 92(Suppl):11381-11388; Sun L, Chang J, Kirchhoff S R et al, Activation of HSF and selective increase in heat-shock proteins by acute dexamethasone treatment. Am J Physiol 2000; 278:HI090-HI097).
The fact remains, however, that no heat shock protein inducer has yet been offered which does a good job of inducing heat shock proteins in the heart and presents no problems in terms of toxicity or side-effects.